Heterocyclic antiviral compounds
a technology of heterocyclic antiviral compounds and compounds, which is applied in the field of non-nucleoside compounds, can solve the problems of limited hcv prevention therapy, no preventive treatment of hepatitis c virus, and currently approved therapies, etc., and achieve the effect of inhibiting hcv replication and inhibiting hcv
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example 1
2-[4-tert-Butyl-5-methoxy-2-(2-oxo-1,2-dihydro-pyridin-3-yl)-benzyl]-isoindole-1,3-dione (I-33) (SCHEME A)
[0143](4-tert-Butyl-3-methoxy-phenyl)-methanol (A-1a)—To a solution of 4-tert-butyl-3-methoxybenzoic acid (3.00 g, 14.40 mmol) in THF (60 mL) cooled to 5° C. was added dropwise a solution of BH3.Me2S (2.0M in THF, 16.60 mL, 33.10 mmol). The reaction was allowed to stir for 24 h at RT then cooled to −50° C. and quenched by dropwise addition of MeOH (20 mL). The reaction mixture was warmed to RT and concentrated in vacuo. The residue was taken up in MeOH (3×20 mL) and concentrated in vacuo. The final residue partitioned between EtOAc and satd. aqueous NaHCO3. The organic layer was washed with water, brine, dried (MgSO4), filtered and concentrated to afford 2.64 g (95%) of A-1a (R2a=R2b=R2c=Me) as a colorless oil.
[0144]step 1—To a solution of A-1a (2.08 g, 10.70 mmol) in CCl4 (75 mL) was added NBS (2.10 g, 11.80 mmol). The reaction was stirred for 15 min then diluted with a cold 10...
example 2
N-[4-tert-Butyl-5-methoxy-2-(2-oxo-1,2-dihydro-pyridin-3-yl)-benzyl]-4-hydroxy-benzamide (I-38)
[0150]
[0151]step 6—A solution of A-3b (0.417 g, 13 mmol, (R′=R2a=R2b=R2c=Me) and sodium azide (0.1 g, 1.56 mmol, 1.2 eq) in DMF (10 mL) was stirred at RT overnight before it was diluted with EtOAc. The organic layer was thrice washed with water, brine, dried (MgSO4), filtered and concentrated to afford 0.425 g (100%) of A-3d.
[0152]step 7—A mixture of A-3d (0.425 g, 1.30 mmol) and PPh3 (0.683 g, 2.60 mmol) in THF (10 mL) and water (1 mL) was stirred overnight at RT then poured into water and acidified with 1N aq HCl. The reaction mixture was extracted with a small amount of DCM. The aqueous layer was adjusted to pH 10 with 3N aq NaOH then twice extracted with EtOAc (2×75 mL). The combined EtOAc extracts was washed with brine, dried (MgSO4), filtered and concentrated to afford 0.330 g (85%) of A-3c (Ra=Rb=H).
[0153]step 8—To a solution of A-3c (30 mg, 0.10 mmol), 4-benzyloxybenzoic acid (22.8...
example 3
2-{[4-tert-Butyl-5-methoxy-2-(2-oxo-1,2-dihydro-pyridin-3-yl)-benzyl]-methanesulfonyl-amino}-ethyl acetate (I-30) and N-[4-tert-butyl-5-methoxy-2-(2-oxo-1,2-dihydro-pyridin-3-yl)-benzyl]-N-(2-hydroxy-ethyl)-methanesulfonamide (I-35)
[0156]
[0157]step 1—To a solution of A-3c (250 mg, 0.83 mmol) in DCM (5 mL) cooled to 0° C. was added TEA (0.15 mL, 1.08 mmol) followed by a solution of MeSO2Cl (77 μL, 0.99 mmol) in DCM (1 mL). The reaction was stirred at RT for 17 h, diluted with DCM and washed with 1N aq HCl. The organic layer was washed sequentially with water and brine, dried (MgSO4), filtered and concentrated to afford 0.313 g (100%) of 12a.
[0158]step 2—To a mixture of 12a (49 mg, 0.13 mmol) in DMF (2 mL) cooled to 0° C. was added NaH (60% in oil dispersion, 6 mg, 0.16 mmol). The reaction mixture was stirred for 30 min then NaI (19 mg, 0.13 mmol) and benzyl 2-bromoethyl ether (35 mg, 0.16 mmol) were added sequentially. The reaction mixture was heated stirred at 65° C. for 3.5 h then ...
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